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Molecular and Cellular Biology

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https://www.readbyqxmd.com/read/28630282/desumoylation-of-gli1-by-senp1-attenuates-sonic-hedgehog-signaling
#1
Huaize Liu, Sen Yan, Jie Ding, Ting-Ting Yu, Steven Y Cheng
Transcriptional output of the Sonic hedgehog morphogenic pathway is orchestrated by three Krüppel family transcription factors, Gli1-3, which undergo extensive post-translational modifications, including ubiquitination and SUMOylation. Here, we report that sentrin-specific peptidase SENP1 is the specific de-SUMOylation enzyme for Gli1. We show that SUMOylation stabilizes Gli1 by competing with ubiquitination at conserved lysine residues, and SUMOylated Gli1 is enriched in the nucleus, suggesting that SUMOylation is a nuclear localization signal for Gli1...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28630281/evidence-of-a-prion-like-transmission-of-p53-amyloid-in-saccharomyces-cerevisiae
#2
Shinjinee Sengupta, Samir K Maji, Santanu K Ghosh
Loss of p53 function is largely responsible for the occurrence of cancer in human. Aggregation of mutant p53 has been found in multiple cancer cell types suggesting a role of aggregation for loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation prone sequence specific peptide PILTIITL derived from p53 and the inactive state was found to be stable for many generations...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28630280/ki-67-contributes-to-normal-cell-cycle-progression-and-inactive-x-heterochromatin-in-p21-checkpoint-proficient-human-cells
#3
Xiaoming Sun, Aizhan Bizhanova, Timothy D Matheson, Jun Yu, Julie L Zhu, Paul D Kaufman
Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here, we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by co-depletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of cell cycle inhibitor p21...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28630279/obesity-and-p16-ink4a-down-regulation-activate-breast-adipocytes-and-promote-their-pro-tumorigenicity
#4
Huda H Al-Khalaf, Mrad Amir, Falah Al-Mohanna, Asma Tulbah, Adher Al-Sayed, Abdelilah Aboussekhra
Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16(INK4A) protein in breast adipocytes, which showed active features and strong pro-carcinogenic potential both in vitro and in orthotopic tumor xenografts, as compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28630278/synthetic-deletion-of-the-interleukin-23-receptor-il-23r-stalk-region-led-to-autonomous-il-23r-homodimerization-and-activation
#5
Thorben M Hummel, Theresa Ackfeld, Marco Schönberg, Gregor Ciupka, Falk Schulz, Anne Oberdoerster, Joachim Grötzinger, Jürgen Scheller, Doreen M Floss
Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses, autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R):IL-12 receptor β1 (IL-12Rβ1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellular membrane proximal FNIII-type domains, which are not involved in cytokine binding but mandatory for signal transduction...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28630277/t-cell-intracellular-antigens-and-hu-antigen-r-antagonistically-modulate-mitochondrial-activity-and-dynamics-by-regulating-optic-atrophy-1-gene-expression
#6
Isabel Carrascoso, José Alcalde, Carmen Sánchez-Jiménez, Paloma González-Sánchez, José M Izquierdo
Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. By contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity...
June 19, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28606933/multitiered-and-cooperative-surveillance-of-mitochondrial-phosphatidylserine-decarboxylase-1
#7
Oluwaseun B Ogunbona, Ouma Onguka, Elizabeth Calzada, Steven M Claypool
Phosphatidylserine decarboxylase 1 (Psd1p), an ancient enzyme that converts phosphatidylserine to phosphatidylethanolamine in the inner mitochondrial membrane, must undergo an autocatalytic self-processing event to gain activity. Autocatalysis severs the protein into a large membrane anchored β subunit that non-covalently associates with the small α subunit on the intermembrane space side of the inner membrane. Here, we determined that a temperature sensitive (ts) PSD1 allele is autocatalytically impaired and that its fidelity is closely monitored throughout its life cycle by multiple mitochondrial quality control proteases...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28606932/cadmium-causes-misfolding-and-aggregation-of-cytosolic-proteins-in-yeast
#8
Therese Jacobson, Smriti Priya, Sandeep K Sharma, Stefanie Andersson, Sofia Jakobsson, Robbe Tanghe, Arghavan Ashouri, Sebastien Rauch, Pierre Goloubinoff, Philipp Christen, Markus J Tamás
Cadmium is a highly poisonous metal and is classified as a human carcinogen. While its toxicity is undisputed, the underlying in vivo molecular mechanisms are not fully understood. Here, we demonstrate that cadmium induces aggregation of cytosolic proteins in living yeast cells. Cadmium primarily targets proteins in the process of synthesis or folding, probably by interacting with exposed thiol groups in not yet folded proteins. On the basis of in vitro and in vivo data, we show that cadmium-aggregated proteins form seeds that increase the misfolding of other proteins...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28606931/the-multiplication-of-ribosomal-p-stalk-proteins-contributes-to-the-fidelity-of-translation
#9
Leszek Wawiórka, Eliza Molestak, Monika Szajwaj, Barbara Michalec-Wawiórka, Mateusz Mołoń, Lidia Borkiewicz, Przemysław Grela, Aleksandra Boguszewska, Marek Tchórzewski
The P-stalk represents a vital element within the ribosomal GTPase-associated-center, which represents a landing platform for translational GTPases. The eukaryotic P-stalk exists as a uL10-(P1-P2)2 pentameric complex, which contains five identical C-terminal domains, one within each protein, and the presence of only one such element is sufficient to stimulate factor-dependent GTP hydrolysis in vitro and to sustain cell viability. The functional contribution of the P-stalk to the performance of the translational machinery in vivo, especially the role of P-protein multiplication, has never been explored...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28606930/foxn1-transcription-factor-in-epithelial-growth-and-wound-healing
#10
Anna I Grabowska, Tomasz Wilanowski
FOXN1 is a pro-differentiation transcription factor in the skin epithelium. Recently it has also emerged as an important player in controlling skin wound healing process as it actively participates in reepithelialization and is thought to be responsible for the scar formation. FOXN1-positivity is also a feature of pigmented keratinocytes, including nevi, and FOXN1 is an attribute of benign epithelial tumors. Lack of FOXN1 favors skin regeneration process which is displayed by nude mice pointing to FOXN1 as a "switch" between regeneration vs...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28606929/targeting-oxygen-sensing-prolyl-hydroxylase-phd-for-metformin-associated-lactic-acidosis-treatment
#11
Tomoko Oyaizu-Toramaru, Tomohiro Suhara, Noriyo Hayakawa, Takashi Nakamura, Akiko Kubo, Shizuka Minamishima, Kyoji Yamaguchi, Takako Hishiki, Hiroshi Morisaki, Makoto Suematsu, Yoji Andrew Minamishima
Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anti-cancer and anti-aging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate transcription factor HIF (hypoxia-inducible factor) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28584195/cdk-dependent-phosphorylation-of-sox2-at-serine-39-regulates-neurogenesis
#12
Shuhui Lim, Akshay Bhinge, Sara Bragado Alonso, Irene Aksoy, Julieta Aprea, Chit Fang Cheok, Federico Calegari, Lawrence W Stanton, Philipp Kaldis
Sox2 is known to be important for neuron formation but the precise mechanism through which it activates a neurogenic program and how this differs from its well-established function in self-renewal remain elusive. Here, we identify a highly conserved Cdk phosphorylation site on serine 39 (S39) in Sox2. In neural stem cells (NSCs), phosphorylation of S39 enhances the ability of Sox2 to negatively regulate neuronal differentiation, while loss of phosphorylation is necessary for chromatin retention of a truncated form of Sox2 generated during neurogenesis...
June 5, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28584194/efficient-and-accurate-translation-initiation-directed-by-tisu-involves-rps3-and-rps10e-binding-and-differential-eif1a-regulation
#13
Ora Haimov, Hadar Sinvani, Franck Martin, Igor Ulitsky, Rafi Emmanuel, Ana Tamarkin-Ben-Harush, Assaf Vardy, Rivka Dikstein
Canonical translation initiation involves ribosomal scanning but short 5' UTR mRNAs are translated in a scanning-independent manner. The extent and mechanism of scanning independent translation is not fully understood. Here we report that short 5' UTR mRNAs constitute a substantial fraction of the translatome. Short 5' UTR mRNAs are enriched with TISU, a 12-nucleotide element directing efficient scanning-independent translation. Comprehensive mutagenesis revealed that each AUG flanking nucleotides of TISU contributes to translational strength but only few are important for accuracy...
June 5, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28584193/let-7-contributes-to-diabetic-retinopathy-but-represses-pathological-ocular-angiogenesis
#14
Qinbo Zhou, Robert J A Frost, Chastain Anderson, Fangkun Zhao, Jing Ma, Bo Yu, Shusheng Wang
The in vivo function of microRNAs (miRNAs or miRs) in diabetic retinopathy (DR) and age-related macular degeneration (AMD) remains unclear. Here we report that let-7 family members are expressed in retinal and choroidal endothelial cells (EC). In ECs, overexpression of let-7 by adenovirus represses EC proliferation, migration, and networking in vitro, while inhibition of the let-7 family with a locked nucleic acid (LNA)-anti-miR has the opposite effect. Mechanistically, silencing of the let-7 target gene HMGA2 mimics the phenotype of let-7 overexpression in ECs...
June 5, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28559431/dna-polymerase-beta-participates-in-mitochondrial-dna-repair
#15
P Sykora, S Kanno, M Akbari, T Kulikowicz, B A Baptiste, G S Leandro, H Lu, J Tian, A May, K A Becker, D L Croteau, D M Wilson, R W Sobol, A Yasui, V A Bohr
We have detected DNA polymerase beta (Polβ), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Polβ in the mitochondria. Using Polβ fragments, mitochondrial-specific protein partners were identified, with the interactors mainly functioning in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1 and TFAM, all of which are mitochondria specific DNA effectors and are known to function in the nucleoid...
May 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28559430/acetylation-of-cavin-1-promotes-lipolysis-in-white-adipose-tissue
#16
Shui-Rong Zhou, Liang Guo, Xu Wang, Yang Liu, Wan-Qiu Peng, Yuan Liu, Xiang-Bo Wei, Xin Dou, Meng Ding, Qun-Ying Lei, Shu-Wen Qian, Xi Li, Qi-Qun Tang
White adipose tissue (WAT) serves as a reversible energy storage depot in the form of lipids in response to nutritional status. Cavin-1, an essential component in the biogenesis of caveolae, is a positive regulator of lipolysis in adipocytes. However, molecular mechanisms of cavin-1 in the modulation of lipolysis remain poorly understood. Here, we showed that cavin-1 was acetylated at lysines 291, 293, and 298 (3K), which was under nutritional regulation in WAT. We further identified GCN5 as the acetyltransferase and Sirt1 as the deacetylase of cavin-1...
May 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28559429/rna-binding-protein-cugbp1-inhibits-liver-cancer-in-a-phosphorylation-dependent-manner
#17
Kyle Lewis, Leila Valanejad, Ashley Cast, Mary Wright, Christina Wei, Polina Iakova, Lauren Stock, Rebekah Karns, Lubov Timchenko, Nikolai Timchenko
Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer which is the neutralization of tumor suppressor activities of an RNA binding protein CUGBP1. The translational activity of CUGBP1 is activated by de-phosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of fatty liver phenotype in young S302A mice. Examination of liver cancer in Diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer which is associated with elimination of the mutant CUGBP1...
May 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28559428/bypass-of-activation-loop-phosphorylation-by-aspartate-836-in-activation-of-the-endoribonuclease-activity-of-ire1
#18
Michael C Armstrong, Sergej Šestak, Ahmed A Ali, Hanan A M Sagini, Max Brown, Karen Baty, Achim Treumann, Martin Schröder
The bifunctional protein kinase-endoribonuclease Ire1 initiates splicing of the mRNA for the transcription factor Hac1 when unfolded proteins accumulate in the endoplasmic reticulum. Activation of Saccharomyces cerevisiae Ire1 coincides with autophosphorylation of its activation loop at S840, S841, T844, and S850. Mass spectrometric analysis of Ire1 expressed in Escherichia coli identified S837 as another potential phosphorylation site in vivo Mutation of all five potential phosphorylation sites in the activation loop decreased, but did not completely abolish, splicing of HAC1 mRNA, induction of KAR2 and PDI1 mRNAs, and expression of a β-galactosidase reporter activated by Hac1(i) Phosphorylation site mutants survive low levels of ER stress better than IRE1 deletions strains...
May 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28533221/cd9-regulates-mhc-ii-trafficking-in-monocyte-derived-dendritic-cells
#19
Vera Rocha-Perugini, Gloria Martínez Del Hoyo, José Maria González-Granado, Marta Ramírez-Huesca, Virginia Zorita, Eric Rubinstein, Claude Boucheix, Francisco Sánchez-Madrid
Antigen presentation by dendritic cells (DCs) stimulates naïve CD4(+) T cells, triggering T cell activation and the adaptive arm of the immune response. Newly synthesized major histocompatibility complex class II molecules (MHC-II) accumulate at MHC-II-enriched endosomal compartments, and are transported to the plasma membrane of DCs after binding to antigenic peptides to enable antigen presentation. In DCs, MHC-II molecules are included in tetraspanin-enriched microdomains (TEMs). However, the role of tetraspanin CD9 in these processes remains largely undefined...
May 22, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28533220/triptolide-assisted-phosphorylation-of-p53-suppresses-inflammation-induced-nf-%C3%AE%C2%BAb-survival-pathways-in-cancer-cells
#20
Li Zheng, Jia Jia, Huifang Dai, Lei Wan, Jian Liu, Lin Hu, Mian Zhou, Michael Qiu, Xufeng Chen, Lufen Chang, Jae Y Kim, Karen Reckamp, Dan J Raz, Zongping Xia, Binghui Shen
Chronic inflammation plays important roles in cancer initiation and progression. Resolving chronic inflammation or blocking inflammatory signal transduction may prevent cancer development. Here, we report that the combined low-dose use of two anti-inflammatory drugs, aspirin and triptolide, reduces spontaneous lung cancer incidence from 70% to 10% in a mouse model. Subsequent studies reveal that such treatment has little effect in resolving chronic inflammatory conditions in the lung, but it significantly blocks NF-κB-mediated expression of proliferation and survival genes in cancer cells...
May 22, 2017: Molecular and Cellular Biology
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